This project is directed towards the clarification of interrelationships between anticancer drugs and treatments and immunological responses against tumors, with a view to obtain leads helpful in exploiting existing or pharmacologically modified tumor immunity in conjunction with chemotherapy. Model systems applicable and relevant to the study of selective effects of anticancer agents on specific components of the immune response to autochthonous and syngeneic tumors will be developed. The effects of anticancer drugs on immune effectors leading to immunosuppression and immunosynergism will be studied both in vivo and in vitro; the emphasis will be on alterations of effector cell functions and interactions during ongoing responses, because these may be particularly relevant to the clinical situation where primary sensitization probably occurs long before diagnosis. The selective reversal of specific immunosuppressive effects of certain drugs by the administration of relevant metabolites will be studied. Complement-dependent and independent cytotoxicity of sensitized cells exposed to drug in vivo or in vitro, primary in vitro immunization, and interactions among components of the immune response will be areas of consideration using autochthonous and syngeneic mammary tumors, and allogeneic leukemic cells, as both antigen and target. Drugs studied will include antifolates, methylglyoxal-bis-guanylhydrazone, arabinosylcytosine, cyclophosphamide, daunorubicin, adriamycin, 5-fluorouracil, vincristine and others. The increased antigenicity of transplantable leukemia sublines resistant to drugs will also be investigated. BIBLIOGRAPHIC REFERENCES: J. Medzihradsky, J. Ehrke and E. Mihich. Time limitations in the reversal by citrovorum factor of methotrexate-induced immunosuppression in mice. Biochem. Pharmacology, 1976, in press. J. Bennett, J. Ehrke, C. Dave and E. Mihich. Prevention by spermidine of the immunosuppression caused by methylglyoxal-bis-guanylhydrazone in mice. Proc. Am. A. Cancer Res. 17:130, 1976.